Recombinant vaccines are of particular importance in human and veterinary medicine for prophylaxis and therapy of infectious and cancerous diseases. It is the aim of an immunization with a recombinant vaccine to induce a specific immune reaction against a defined antigen, which is effective in prevention or therapy of defined diseases. Known recombinant vaccines are based on recombinant proteins, synthetic peptide fragments, recombinant viruses, or nucleic acids.
Most of the recombinant vaccines can be divided into two categories: a) vaccines inducing a humoral B cell-mediated immune response which result in specific antibody production, and b) vaccines inducing cellular T-cell mediated immune responses, in particular cytotoxic T-lymphocytes.
Induction of antibodies by preventive vaccination against infectious diseases (e.g., vaccinations against children's diseases) is one of the most effective medical interventions and has been applied successfully for many years. Recently, it also has been shown that the therapeutic passive administration of monoclonal antibodies (mAb) directed against self-proteins represents an effective therapy method of acute and chronic diseases such as cancers or rheumatoid arthritis. Examples for mAb targeted structures are the soluble protein tumor necrosis factor alpha (TNF-α) for rheumatoid arthritis, Crohn's disease and psoriasis (mAb preparation: Infliximab and Adalimumab), as well as the cell surface proteins CD20 for non-Hodgkin lymphoma (mAb preparation: e.g., Rituximab) and HER2/neu receptor (mAb preparation: Trastuzumab [Herceptin]) for breast cancer.
The generation of monoclonal immunotherapeutically effective antibodies (using hybridoma or phage display techniques and subsequent chimerization and humanization, respectively), however, is time consuming and cost intensive which has prevented a broad clinical application so far. Thus, there is an urgent need to provide a possibility for active vaccination against self-molecules instead of the passive administration of monoclonal antibodies. In contrast to passive immunization, during active vaccination the patient's own immune system is induced to produce antibodies. The induced individualized immune response thus circumvents problems of the monoclonal antibody therapy such as intolerance or non-responsiveness to the therapy.
The active induction of a humoral immune response against self-proteins, however, requires that the immunological self-tolerance is broken. Self-proteins or peptides thereof are only very weekly immunogenic due to the immunological tolerance against self-proteins. Existing immunization strategies based on recombinant proteins or synthetic peptide fragments for induction of antibody responses against self-proteins are thus based on concomitant administration of the antigen in combination with immunostimulatory adjuvants. Many potently effective adjuvants, however, exhibit the disadvantage of undesirable side effects such as toxicity, inflammation reactions, or unwanted systemic T-cell response, and thus, their use should be avoided for active vaccination strategies.
There are certain requirements for an active immunotherapeutically effective vaccination such as breaking self-tolerance against self-proteins, avoidance of adjuvants, antibody specificity against proteins in their native conformation, and induction of antibodies with immune effector functions.
Another essential factor for a successful active vaccination in the context of an antibody-mediated cancer immunotherapy is the selection of an appropriate tumor target structure.
Basic requirements for the target structure are tumor-specificity and cell surface localization. This allows for selective binding of the induced antibodies to the tumor cells and allows for directed exertion of effector functions of the antibody against these cells. Particularly interesting tumor-associated antigens are the so-called cell type specific differentiation antigens. Their expression is limited to cells of a particular specificity and developmental stage in normal tissues. However, in many cancerous diseases, these antigens are expressed in the tumorigenic tissue.
There is an urgent need for the development of means which allow for self-tolerance breaking active immunization without the need of administering adjuvants. In particular, there is a need for the development of means that allow for the generation of antibodies with effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), induction of apoptosis, and inhibition of proliferation, in vivo, wherein said antibodies are directed against a self-protein, such as a tumor-associated antigen.
The present invention relates to the development of vaccines for active vaccination which are able to induce antibodies, in particular autoantibodies, in an organism which bind to self cell membrane surface antigens in their native conformation and subsequently exert therapeutically effective effector functions on cells carrying said cell membrane surface antigens.
The development of cancer immunotherapeutic vaccines is exemplarily described for the target structures claudin 18.2 (CLDN18.2), claudin 6 (CLDN6), and PLAC1, respectively. The generated vaccines are capable of inducing an effective humoral immune response which breaks the present immunological self-tolerance, without concomitant administration of adjuvants. The induced antibodies are further able to recognize the proteins in their native conformation and exert therapeutically relevant effector functions such as ADCC and/or CDC.